(150m) Thermally Induced in Situ Formation of Polymersomes with Sustained Release of Tetrodotoxin

Injectable local anesthetics that provide a continuous nerve block approximating the duration of pain states could offer significant benefits for patients experiencing post-operative or chronic pain. Tetrodotoxin (TTX), a site-1 sodium channel blocker, has been investigated as an alternative to conventional anesthetics due to its potent local anesthetic effects and limited toxicity. However, the poor encapsulation of hydrophilic small molecules, such as TTX, can cause drug leakage during storage or a rapid initial release upon administration, resulting in systemic toxicity and limited efficacy. In addition, traditional drug carriers (i.e., polymersome and liposome) can be cumbersome to fabricate. To address these shortcomings, we developed thermally-induced in situ-forming polymersomes based on hyperbranched polyglycerol-poly(propylene glycol)-poly(ethylene glycol)-poly(propylene glycol)-hyperbranched polyglycerol (HPG-PPG-PEG-PPG-HPG) copolymers. Specifically, hydrophilic molecules were simply co-dissolved with the thermally sensitive copolymers in an aqueous solution, and no additional steps that might cause loss of payload were involved before injection. Upon in vivo injection, the polymersomes self-assembled in situ through a phase transition upon temperature increase above the lower critical solution temperature (LCST), resulting in physical encapsulation of the drug molecules with an encapsulation efficiency of up to 90%. The formed polymersomes contained microscopically visible internal aqueous pockets. In vivo studies showed that the HPG-31R1-HPG/TTX polymersomes provided sustained release of TTX and prolonged sensory nerve block duration. In Sprague–Dawley rats, a single injection of the HPG-31R1-HPG polymersome containing 8 µg of TTX produced sensory nerve block lasting up to 6 hours, without any TTX-related systemic toxicity or tissue toxicity to nerves and muscles.